Neuropeptide Y (NPY) is the most potent orexigenic, naturally-occurring signal known. Our previous studies showed that when feeding is desired NPY is released at a high rate into the paraventricular nucleus (PVN) of the hypothalamus and as rats consumed food, NPY hypersecretion ceased. Based on our recent findings, we now propose to test the hypothesis that an interconnected orexigenic network exists in the rat hypothalamus and that the NPY system exerts a regulatory influence in this circuitry. Aim i is to identify the cellular and molecular events in the dynamics of NPY secretion (synthesis, storage and release) in association with food intake. After obtaining this basic information, Aim 2 will evaluate how the interconnected orexigenic network operates. Aim 3 is to validate the hypothesis that the cessation of NPY hypersecretion in the PVN that occurs in association with food consumption is due to the inhibitory action of locally-produced peptides. The release, synthesis and postsynaptic effects of the peptidergic components of the newly identified orexigenic network will be assessed in vivo and in vitro. The sequential studies in this proposal are designed to first identify the important signals that stimulate or inhibit feeding and then to understand the mechanism of their action and of the factors that regulate their release and synthesis. Information gained from these studies should unravel the operation, physiological roles and relationships of three peptide signals that comprise the newly identified excitatory orexigenic network and form the basis for future studies to elucidate the etiology of certain eating disorders and obesity of hypothalamic origin.